Biomarkers and genetic modulators of cerebral vasculopathy in sub-Saharan ancestry children with sickle cell anemia

Abstract

We investigated biomarkers and genetic modulators of the cerebral vasculopathy (CV) subphenotype in pediatric sickle cell anemia (SCA) patients of sub-Saharan African ancestry. We found that one VCAM1 promoter haplotype (haplotype 7) and VCAM1 single nucleotide variant rs1409419_T were associated with stroke events, stroke risk, as measured by time-averaged mean of maximum velocity in the middle cerebral artery, and with high serum levels of the hemolysis biomarker lactate dehydrogenase. Furthermore, VCAM-1 ligand coding gene ITGA4 variants rs113276800_A and rs3770138_T showed a positive association with stroke events. An additional positive relationship between a genetic variant and stroke risk was observed for ENPP1 rs1044498_A. Conversely, NOS3 variants were negatively associated with silent cerebral infarct events (VNTR 4b_allele and haplotype V) and CV globally (haplotype VII). The -alpha 3.7kb -thal deletion did not show association with CV. However, it was associated with higher red blood cell and neutrophil counts, and lower mean corpuscular volume, mean corpuscular hemoglobin and red cell distribution width.Our results underline the importance of genetic modulators of the CV sub-phenotype and their potential as SCA therapeutic targets. We also propose that a biomarker panel comprising biochemical, hematological, imaging and genetic data would be instrumental for CV prediction, and prevention.

Genetic Variation and Sickle Cell Disease Severity

“…A total of 571 publications passed this screening (eFigure 1 in Supplement 1 , eTable 1 in Supplement 2 ). 8 , 11 , 12 , 13 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ...…”

Genetic modulation of anemia severity, hemolysis level, and hospitalization rate in Angolan children with Sickle Cell Anemia

“…Sickle RBCs have a propensity to adhere to endothelial VCAM-1 via Very Late Antigen-4 expressed on their membrane surface [14]. Thus, it has been accepted that VCAM1 gene variants could be modulators of phenotypic differences in SCA, and several polymorphisms in VCAM1 covering both the gene and its promoter have already been studied in the context of this pathology [16][17][18][19][20]. Amongst the six VCAM1 promoter variants investigated in our study, the rs1041163 T > C stands out.…”

“…Therefore, in SCD patients, the sialoglycoprotein vascular cell adhesion molecule-1, encoded by VCAM1 gene, is highly expressed at the surface of endothelial cells of both large and small vessels, following cytokine stimulation, and sickle RBCs are particularly prone to adhere to them [11][12][13][14]. Several VCAM1 variants have been studied and associated to phenotypic differences between SCA patients, individually or grouped in haplotypes [15][16][17][18][19][20]. In addition, under hypoxic conditions, the polymerization of HbS and sickling of RBCs cause alterations in their cell membrane properties, leading to reduced cellular deformability and unusual cell adherence to the vascular endothelium.…”

Association of laboratory markers and cerebral blood flow among sickle cell anemia children

“…Based on the evidence, blood velocity greater than or equal to 200 cm/s is considered a stroke risk condition (17,18). Currently, some predictors are considered classic markers, such as severe anemia, leukocytosis, nocturnal hypoxemia, and genetic factors (7,19,20). Several studies have been conducted to identify risk factors associated with CVA in individuals with SCA (21)(22)(23)(24).…”